Organocatalytic asymmetric mannich-type reactions: an easy approach to optically active amine derivatives

The topics I came across during the period I spent as a Ph.D. student are mainly two. The first concerns new organocatalytic protocols for Mannich-type reactions mediated by Cinchona alkaloids derivatives (Scheme I, left); the second topic, instead, regards the study of a new approach towards the enantioselective total synthesis of Aspirochlorine, a potent gliotoxin that recent studies indicate as a highly selective and active agent against fungi (Scheme I, right). At the beginning of 2005 I had the chance to join the group of Prof. Alfredo Ricci at the Department of Organic Chemistry of the University of Bologna, starting my PhD studies. During the first period I started to study a new homogeneous organocatalytic aza-Henry reaction by means of Cinchona alkaloid derivatives as chiral base catalysts with good results. Soon after we introduced a new protocol which allowed the in situ synthesis of N-carbamoyl imines, scarcely stable, moisture sensitive compounds. For this purpose we used α-amido sulfones, bench stable white crystalline solids, as imine precursors (Scheme II). In particular we were able to obtain the aza-Henry adducts, by using chiral phase transfer catalysis, with a broad range of substituents as R-group and excellent results, unprecedented for Mannich-type transformations (Scheme II). With the optimised protocol in hand we have extended the methodology to the other Mannich-type reactions. We applied the new method to the Mannich, Strecker and Pudovik (hydrophosphonylation of imines) reactions with very good results in terms of enantioselections and yields, broadening the usefulness of this novel protocol. The Mannich reaction was certainly the most extensively studied work in this thesis (Scheme III). Initially we developed the reaction with α-amido sulfones as imine precursors and non-commercially available malonates with excellent results in terms of yields and enantioselections.3 In this particular case we recorded 1 mol% of catalyst loading, very low for organocatalytic processes. Then we thought to develop a new Mannich reaction by using simpler malonates, such as dimethyl malonate.4 With new optimised condition the reaction provided slightly lower enantioselections than the previous protocol, but the Mannich adducts were very versatile for the obtainment of β3-amino acids. Furthermore we performed the first addition of cyclic β-ketoester to α-amido sulfones obtaining the corresponding products in good yield with high level of diastereomeric and enantiomeric excess (Scheme III). Further studies were done about the Strecker reaction mediated by Cinchona alkaloid phase-transfer quaternary ammonium salt derivatives, using acetone cyanohydrin, a relatively harmless cyanide source (Scheme IV). The reaction proceeded very well providing the corresponding α-amino nitriles in good yields and enantiomeric excesses. Finally, we developed two new complementary methodologies for the hydrophosphonylation of imines (Scheme V). As a result of the low stability of the products derived from aromatic imines, we performed the reactions in mild homogeneous basic condition by using quinine as a chiral base catalyst giving the α-aryl-α-amido phosphonic acid esters as products (Scheme V, top).6 On the other hand, we performed the addition of dialkyl phosphite to aliphatic imines by using chiral Cinchona alkaloid phase transfer quaternary ammonium salt derivatives using our methodology based on α-amido sulfones (Scheme V, bottom). The results were good for both procedures covering a broad range of α-amino phosphonic acid ester. During the second year Ph.D. studies, I spent six months in the group of Prof. Steven V. Ley, at the Department of Chemistry of the University of Cambridge, in United Kingdom. During this fruitful period I have been involved in a project concerning the enantioselective synthesis of Aspirochlorine. We provided a new route for the synthesis of a key intermediate, reducing the number of steps and increasing the overall yield. Then we introduced a new enantioselective spirocyclisation for the synthesis of a chiral building block for the completion of the synthesis (Scheme VI).

Seismic tomographic full-waveform inversion for the Vrancea sinking lithosphere structure using the adjoint method.

The Vrancea region, at the south-eastern bend of the Carpathian Mountains in Romania, represents one of the most puzzling seismically active zones of Europe. Beside some shallow seismicity spread across the whole Romanian territory, Vrancea is the place of an intense seismicity with the presence of a cluster of intermediate-depth foci placed in a narrow nearly vertical volume. Although large-scale mantle seismic tomographic studies have revealed the presence of a narrow, almost vertical, high-velocity body in the upper mantle, the nature and the geodynamic of this deep intra-continental seismicity is still questioned. High-resolution seismic tomography could help to reveal more details in the subcrustal structure of Vrancea. Recent developments in computational seismology as well as the availability of parallel computing now allow to potentially retrieve more information out of seismic waveforms and to reach such high-resolution models. This study was aimed to evaluate the application of a full waveform inversion tomography at regional scale for the Vrancea lithosphere using data from the 1999 six months temporary local network CALIXTO. Starting from a detailed 3D Vp, Vs and density model, built on classical travel-time tomography together with gravity data, I evaluated the improvements obtained with the full waveform inversion approach. The latter proved to be highly problem dependent and highly computational expensive. The model retrieved after the first two iterations does not show large variations with respect to the initial model but remains in agreement with previous tomographic models. It presents a well-defined downgoing slab shape high velocity anomaly, composed of a N-S horizontal anomaly in the depths between 40 and 70km linked to a nearly vertical NE-SW anomaly from 70 to 180km.

Towards the 3D attenuation imaging of active volcanoes: methods and tests on real and simulated data

The purpose of my PhD thesis has been to face the issue of retrieving a three dimensional attenuation model in volcanic areas. To this purpose, I first elaborated a robust strategy for the analysis of seismic data. This was done by performing several synthetic tests to assess the applicability of spectral ratio method to our purposes. The results of the tests allowed us to conclude that: 1) spectral ratio method gives reliable differential attenuation (dt*) measurements in smooth velocity models; 2) short signal time window has to be chosen to perform spectral analysis; 3) the frequency range over which to compute spectral ratios greatly affects dt* measurements. Furthermore, a refined approach for the application of spectral ratio method has been developed and tested. Through this procedure, the effects caused by heterogeneities of propagation medium on the seismic signals may be removed. The tested data analysis technique was applied to the real active seismic SERAPIS database. It provided a dataset of dt* measurements which was used to obtain a three dimensional attenuation model of the shallowest part of Campi Flegrei caldera. Then, a linearized, iterative, damped attenuation tomography technique has been tested and applied to the selected dataset. The tomography, with a resolution of 0.5 km in the horizontal directions and 0.25 km in the vertical direction, allowed to image important features in the off-shore part of Campi Flegrei caldera. High QP bodies are immersed in a high attenuation body (Qp=30). The latter is well correlated with low Vp and high Vp/Vs values and it is interpreted as a saturated marine and volcanic sediments layer. High Qp anomalies, instead, are interpreted as the effects either of cooled lava bodies or of a CO2 reservoir. A pseudo-circular high Qp anomaly was detected and interpreted as the buried rim of NYT caldera.

Multi-scale analysis of active landslides using two-pass differential interferometry

Landslides are common features of the landscape of the north-central Apennine mountain range and cause frequent damage to human facilities and infrastructure. Most of these landslides move periodically with moderate velocities and, only after particular rainfall events, some accelerate abruptly. Synthetic aperture radar interferometry (InSAR) provides a particularly convenient method for studying deforming slopes. We use standard two-pass interferometry, taking advantage of the short revisit time of the Sentinel-1 satellites. In this paper we present the results of the InSAR analysis developed on several study areas in central and Northern Italian Apennines. The aims of the work described within the articles contained in this paper, concern: i) the potential of the standard two-pass interferometric technique for the recognition of active landslides; ii) the exploration of the potential related to the displacement time series resulting from a two-pass multiple time-scale InSAR analysis; iii) the evaluation of the possibility of making comparisons with climate forcing for cognitive and risk assessment purposes. Our analysis successfully identified more than 400 InSAR deformation signals (IDS) in the different study areas corresponding to active slope movements. The comparison between IDSs and thematic maps allowed us to identify the main characteristics of the slopes most prone to landslides. The analysis of displacement time series derived from monthly interferometric stacks or single 6-day interferograms allowed the establishment of landslide activity thresholds. This information, combined with the displacement time series, allowed the relationship between ground deformation and climate forcing to be successfully investigated. The InSAR data also gave access to the possibility of validating geographical warning systems and comparing the activity state of landslides with triggering probability thresholds.

Hierarchical active inference for cognitive architectures

This thesis explores the methods based on the free energy principle and active inference for modelling cognition. Active inference is an emerging framework for designing intelligent agents where psychological processes are cast in terms of Bayesian inference. Here, I appeal to it to test the design of a set of cognitive architectures, via simulation. These architectures are defined in terms of generative models where an agent executes a task under the assumption that all cognitive processes aspire to the same objective: the minimization of variational free energy. Chapter 1 introduces the free energy principle and its assumptions about self-organizing systems. Chapter 2 describes how from the mechanics of self-organization can emerge a minimal form of cognition able to achieve autopoiesis. In chapter 3 I present the method of how I formalize generative models for action and perception. The architectures proposed allow providing a more biologically plausible account of more complex cognitive processing that entails deep temporal features. I then present three simulation studies that aim to show different aspects of cognition, their associated behavior and the underlying neural dynamics. In chapter 4, the first study proposes an architecture that represents the visuomotor system for the encoding of actions during action observation, understanding and imitation. In chapter 5, the generative model is extended and is lesioned to simulate brain damage and neuropsychological patterns observed in apraxic patients. In chapter 6, the third study proposes an architecture for cognitive control and the modulation of attention for action selection. At last, I argue how active inference can provide a formal account of information processing in the brain and how the adaptive capabilities of the simulated agents are a mere consequence of the architecture of the generative models. Cognitive processing, then, becomes an emergent property of the minimization of variational free energy.

Active control of sound radiated by vibrating surfaces on a McLaren supercar

Sound radiators based on forced vibrations of plates are becoming widely employed, mainly for active sound enhancement and noise cancelling systems, both in music and automotive environment. Active sound enhancement solutions based on electromagnetic shakers hence find increasing interest. Mostly diffused applications deal with active noise control (ANC) and active vibration control systems for improving the acoustic experience inside or outside the vehicle. This requires investigating vibrational and, consequently, vibro-acoustic characteristics of vehicles. Therefore, simulation and processing methods capable of reducing the calculation time and providing high-accuracy results, are strongly demanded. In this work, an ideal case study on rectangular plates in fully clamped conditions preceded a real case analysis on vehicle panels. The sound radiation generated by a vibrating flat or shallow surface can be calculated by means of Rayleigh’s integral. The analytical solution of the problem is here calculated implementing the equations in MATLAB. Then, the results are compared with a numerical model developed in COMSOL Multiphysics, employing Finite Element Method (FEM). A very good matching between analytical and numerical solutions is shown, thus the cross validation of the two methods is achieved. The shift to the real case study, on a McLaren super car, led to the development of a mixed analytical-numerical method. Optimum results were obtained with mini shakers excitement, showing good matching of the recorded SPL with the calculated one over all the selected frequency band. In addition, a set of directivity measurements of the hood were realized, to start studying the spatiality of sound, which is fundamental to active noise control systems.